This invention relates to inhibitors of the family tyrosine kinase, and particularly, inhibitors of Bruton""s Tyrosine Kinase (BTK). This invention also relates to methods for the treatment of asthma in mammals with LFM analogues, particularly, with the LFM analogue A8 (LFM-A8).
Apoptosis is a common mode of eukaryotic cell death which is triggered by an inducible cascade of biochemical events leading to activation of endonucleases that cleave the nuclear DNA into oligonucleosome-length fragments. Several of the biochemical events that contribute to apoptotic cell death as well as both positive and negative regulators of apoptosis have recently been identified (Whyllie A., et al. (1980) Int. Rev. Cytol. 68, 251-305; Steller H., (1995) Science 267, 1445-1449; Fraser, A., Evan, G. (1996) Cell 85, 781-784; and Korsmeyer, S. J. (1995). Trends Genet. 11, 101-105). Apoptosis plays a pivotal role in the development and maintenance of a functional immune system by ensuring the timely self-destruction of autoreactive immature and mature lymphocytes as well as any emerging target neoplastic cells by cytotoxic T cells.
In addition to the beneficial effects associated with apoptosis, inappropriate apoptosis contributes to the pathogenesis and drug resistance of human leukemias and lymphomas (Cohen, J. J., et al. (1992)Annu. Rev. Immunol. 10, 267-293; Linette, G. P., Korsmeyer, S. J. (1994) Curr. Opin. Cell Biol. 6, 809-815; and Thompson, C. B. (1995)Science 367, 1456-1462). Thus, agents that are useful to modulate apoptosis are potentially useful as therapeutic agents for treating diseases in which inappropriate apoptosis is implicated. As a result, there is a considerable amount of ongoing research devoted to the identification of molecular regulators of apoptosis, and there is currently a need for novel agents (e.g. chemical or biological), and novel therapeutic methods, that are useful for modulating apoptosis. Such agents and methods may be useful for treating cancer (e.g. leukemias and lymphomas) or immune disorders in mammals. They may also be useful as pharmacolocical tools for use in in vitro or in vivo studies to enhance the understanding of the molecular basis of apoptosis (e.g. the pro-apoptotic versus the anti-apoptotic regulatory signal), as well as the pathogenesis of human lymphoid malignancies.
Asthma, which affects the respiratory tract, is characterized by bronchoconstriction and hyperresponsiveness of the airway passages and is brought about by various stimulating agents. Physiological effects of asthma include smooth muscle contraction of the airway, increased bronchial mucus secretion, and inflammation. These effects lead to symptoms commonly associated with asthma. Over 10 million people in the United States have asthma and the medically-related costs associated with asthma are estimated at over $5 billion annually.
The immune system, cued by environmental allergens, is likely to play a role in generating asthmatic conditions. Such conditions involve the transient enhancement of airway hyperresponsiveness triggered by inhaled allergens. The hyperresponsiveness is associated with airway inflammation brought about by smooth muscle contractions in the bronchioles.
Inhaled allergens can initiate the inflammatory sequence in an allergic response. Leukocytes displaying IgE receptors, particularly mast cells and basophils, are present in the epithelium and bronchiolar smooth muscle. These cells are activated by binding specific inhaled antigens to the IgE receptors. Activated mast cells release a number of preformed or primary chemical mediators of the inflammatory response, such as leukotrienes. The airway (bronchiolar) constriction that occurs soon after allergen exposure is likely to be a result of this chemical release from mast cells. Later in the asthmatic reaction, a substantial increase in the number of inflammatory cells which infiltrate bronchiolar smooth muscle and epithelial tissues is observed. Lymphocytes, neutrophils and eosinophils are attracted to the bronchioles by chemicals released from activated mast cells.
Historically, bronchodilator drugs have been used to relieve the bronchoconstriction associated with asthma. However, more recently, anti-inflammatory drugs, which target many of the cellular types involved in asthmatic reactions, as listed above, have begun to replace bronchodilators as first-line treatments for asthma.
The invention provides inhibitors of Tec family tyrosine kinases, and particularly of BTK. The inhibitors of the invention are useful in the treatment of pathologic conditions involving cells expressing Tec family tyrosine kinaes, such as Tcells (Tec, Itk) and B cells (BTK).
The invention provides compounds of formula I: 
where:
R1 is (C1-C3)alkyl, (C3-C6)cycloalkyl, phenyl, or NRaRb;
R2 is hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy amino (C2-C5)alkoxy; hydroxy (C2-C5)alkoxy amino (C2-C5)alkanoxy; or hydroxy (C2-C5) alkanoxy;
R3 is cyano or (C1-C3)alkanoyl;
R4 is hydrogen, (C1-C3)alkyl; hydroxy (C2-C5)alkyl; or amino (C2-C5)alkyl;
R5 is aryl, or heteroaryl;
Ra and Rb are each independently hydrogen, or (C1-C3)alkyl; or Ra and Rb together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;
wherein any aryl, or heteroaryl of R1 and R5 is optionally substituted with one or more (e.g. 1, 2, or 3) substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3)alkanoyl, xe2x80x94S(O)2Rc, or NRaRb; wherein Rc is (C1-C3)alkyl, or aryl
or a pharmaceutically acceptable salt thereof;
provided that if R5 is phenyl, the phenyl is substituted by xe2x80x94S(O)2Rc, or is substituted by halo and at least one other substituent.
The invention provides a method to alter leukotriene production from mast cells, comprising contacting mast cells with an effective leukotriene-altering amount of a LFM analogue.
The invention provides a method for treating or preventing asthma in a mammal comprising administering to a mammal a therapeutically effective amount of a LFM analogue. The invention also provides a method for altering the number of eosinophils in the bronchioles and for reducing bronchial hyperresponsiveness comprising administering to a mammal a therapeutically effective amount of a LFM analogue.
The invention provides a compound of formula Ia: 
where X is defined to be H, Br, Cl, F, CF3, or OCF3.
The invention also provides a compound of formula II: 
where:
X is O, N, or S;
R1 is H, alkyl, carboxyl,
preferably C1-C3 alkyl or C1-C3 carboxyl; and
R2 is alkyl, preferably C1-C6 alkyl.
The compounds of the invention are designed to fit a composite binding pocket model of the BTK domain, having a molecular volume of less than the volume of the binding pocket (e.g., less than about 600 xc3x853) and preferably a volume that approaches ⅔ the volume of the pocket, e.g., approximately 400 xc3x853. Most preferably, the inhibitors of the invention are designed to fille the space of the binding pocket and to interact with residues of the pocket for enhanced binding.
The invention also provides a pharmaceutical composition comprising an agent that inhibits or prevents the action of Bruton""s tyrosine kinase; and a pharmaceutically acceptable carrier.
The invention also provides a method to promote or induce apoptosis in a BTK expressing cell comprising contacting the cell with an agent that inhibits or prevents the action of BTK.
The invention also provides a method to treat a disease (pathologic condition) wherein BTK is implicated and inhibition of its action is desired comprising administering to a mammal in need of such treatment an effective amount of an agent that inhibits or prevents the action of BTK.
The invention also provides a method to lower the resistance of a BTK expressing cell to drug therapy comprising contacting the cell with an agent that inhibits or prevents the action of BTK.
The invention provides a BTK inhibitor for use in medical therapy (preferably for use in treating cancer or other BTK mediated diseases), as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with BTK (e.g. cancer, such as a leukemia or a lymphoma).